IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss
Open accessAbstract
Transcription factor, nuclear factor κB (NF-κB), is required for osteoclast formation in vivo and mice lacking both of the NF-κB p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the IκB kinase (IKK) complex that mediate NF-κB activation, IKKα and IKKβ, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKβ subunit as a transducer of signals from receptor activator of NF-κB (RANK) to NF-κB. Although IKKα is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKβ is required for osteoclastogenesis in vitro and in vivo. IKKβ also protects osteoclasts and their progenitors from tumor necrosis factor α–induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.
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Global deletion of single molecules involved in the Nf-κB noncanonical pathway did not affect osteoclast numbers in vivo.
“Global deletion of single molecules involved in the Nf-κB noncanonical pathway did not affect osteoclast numbers in vivo,170”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [170]
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Cites
Takeda, K., Kaisho, T., & Akira, S. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141126 · Cited by 6,143 · see citing works
Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.
Lacey, D. L., Timms, E., Tan, H.-L., Kelley, M. J., Dunstan, C. R., Burgess, T., Elliott, R., Colombero, A., Elliott, G., Scully, S., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81569-x · Cited by 5,439 · see citing works
PARFITT, A. M., Drezner, M. K., Glorieux, F. H., Kanis, J. А., Malluche, H. H., Meunier, P. J., Ott, S. M., & Recker, R. R. (1987) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.5650020617 · Cited by 5,015 · see citing works
Missing Pieces in the NF-κB Puzzle
Ghosh, S., & Karin, M. (2002) · Cell · doi:10.1016/s0092-8674(02)00703-1 · Cited by 3,638 · cited 9× · see citing works
“NF- B also is activated by the proinflammatory cytokines, TNF and IL-1 (21), which enhance inflammation-induced bone loss, although they are not essential for developmental osteoclastogenesis (41, 42).”
InfluentialSelf-citationOPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis.
Kong, Y.-Y., Yoshida, H., Sarosi, I., Tan, H.-L., Timms, E., Capparelli, C., Morony, S., Oliveira-dos-Santos, A. J., Van, G., Itie, A., et al. (1999) · Nature · doi:10.1038/16852 · Cited by 3,351 · see citing works
Bone Histomorphometry : Standardization of Nomenclature, Symbols, and Units
PARFITT, A. M., Drezner, M. K., Glorieux, F. H., Kanis, J. А., Malluche, H. H., Meunier, P. J., Ott, S. M., & Recker, R. R. (1987) · Journal of Bone and Mineral Research · Cited by 3,258 · see citing works
NF-κB at the crossroads of life and death
Karin, M., & Lin, A. (2002) · Nature Immunology · doi:10.1038/ni0302-221 · Cited by 2,709 · see citing works
Self-citationThe Regulation of AP-1 Activity by Mitogen-activated Protein Kinases
Karin, M. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.28.16483 · Cited by 2,432 · see citing works
Self-citationSuda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M. T., & Martin, T. J. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.3.0367 · Cited by 2,317 · see citing works
A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function.
Anderson, D. M., Maraskovsky, E., Billingsley, W. L., Dougall, W. C., Tometsko, M. E., Roux, E. R., Teepe, M. C., DuBose, R. F., Cosman, D., & Galibert, L. (1997) · Nature · doi:10.1038/36593 · Cited by 2,290 · see citing works
A cytokine-responsive IκB kinase that activates the transcription factor NF-κB
DiDonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E., & Karin, M. (1997) · Nature · doi:10.1038/41493 · Cited by 2,125 · see citing works
Self-citationTargeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice
Soriano, P. M., Montgomery, C. A., Geske, R. S., & Bradley, A. (1991) · Cell · doi:10.1016/0092-8674(91)90499-o · Cited by 1,997 · see citing works
Inducible Gene Targeting in Mice
Kühn, R., Schwenk, F., Aguet, M., & Rajewsky, K. (1995) · Science · doi:10.1126/science.7660125 · Cited by 1,915 · see citing works
Signal transduction by tumor necrosis factor and its relatives.
Baud, V., & Karin, M. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)02064-5 · Cited by 1,741 · see citing works
Self-citationManolagas, S. C., & Jilka, R. L. (1995) · New England Journal of Medicine · doi:10.1056/nejm199502023320506 · Cited by 1,684 · see citing works
Reaching a Genetic and Molecular Understanding of Skeletal Development
Karsenty, G., & Wagner, E. F. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00157-0 · Cited by 1,594 · see citing works
Self-citationRANK is essential for osteoclast and lymph node development.
Dougall, W. C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., Daro, E., Smith, J., Tometsko, M. E., Maliszewski, C. R., et al. (1999) · Genes & Development · doi:10.1101/gad.13.18.2412 · Cited by 1,478 · see citing works
Lam, J., Takeshita, S., Barker, J. E., Kanagawa, O., Ross, F. P., & Teitelbaum, S. L. (2000) · Journal of Clinical Investigation · doi:10.1172/jci11176 · Cited by 1,440 · cited 1× · see citing works
“However, it remains controversial whether TNF promotes osteoclastogenesis independently of RANKL (10, 11).”
BackgroundLi, P., Allen, H., Banerjee, S., Franklin, S., Herzog, L., Johnston, C. G., McDowell, J., Paskind, M. P., Rodman, L., Salfeld, J. G., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90490-5 · Cited by 1,408 · see citing works
Activation by IKKα of a Second, Evolutionary Conserved, NF-κB Signaling Pathway
Senftleben, U., Cao, Y., Xiao, G., Greten, F. R., Krähn, G. M., Bonizzi, G., Chen, Y., Hu, Y., Fong, A., Sun, S., et al. (2001) · Science · doi:10.1126/science.1062677 · Cited by 1,361 · see citing works
Self-citationT-Cell mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ.
Takayanagi, H., Ogasawara, K., Hida, S., Chiba, T., Murata, S., Sato, K., Takaoka, A., Yokochi, T., Oda, H., Tanaka, K., et al. (2000) · Nature · doi:10.1038/35046102 · Cited by 1,358 · see citing works
Kobayashi, K., Takahashi, N., Jimi, E., Udagawa, N., Takami, M., Kotake, S., Nakagawa, N., Kinosaki, M., Yamaguchi, K., Shima, N., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.2.275 · Cited by 1,304 · see citing works
c-Fos: a Key Regulator of Osteoclast-Macrophage Lineage Determination and Bone Remodeling
Grigoriadis, A. E., Wang, Z., Cecchini, M. G., Hofstetter, W., Felix, R., Fleisch, H. A., & Wagner, E. F. (1994) · Science · doi:10.1126/science.7939685 · Cited by 1,260 · see citing works
Self-citationTRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signalingPreprint
Lomaga, M. A., Yeh, W., Sarosi, I., Duncan, G. S., Furlonger, C. L., Ho, A. P., Morony, S., Capparelli, C., Van, G. Y., Kaufman, S., et al. (1999) · Genes & Development · doi:10.1101/gad.13.8.1015 · Cited by 1,253 · see citing works
Rothe, J., Lesslauer, W., Loetscher, H., Lang, Y., Koebel, P., Köntgen, F., Althage, A., Zinkernagel, R. M., Steinmetz, M., & Bluethmann, H. (1993) · Nature · doi:10.1038/364798a0 · Cited by 1,246 · see citing works
Udagawa, N., Takahashi, N., Akatsu, T., Tanaka, H., Sasaki, T., Nishihara, T., Koga, T., Martin, T. J., & Suda, T. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.18.7260 · Cited by 1,048 · see citing works
Requirement for NF-κB in osteoclast and B-cell development
Franzoso, G., Carlson, L., Xing, L., Poljak, L., Shores, E. W., Brown, K. D., Leonardi, A., Tran, T., Boyce, B. F., & Siebenlist, U. (1997) · Genes & Development · doi:10.1101/gad.11.24.3482 · Cited by 996 · see citing works
Osteopetrosis in mice lacking NF-κB1 and NF-κB2
Iotsova, V., Caamaño, J., Loy, J. K., Yang, Y., Lewin, A. C., & Bravo, R. (1997) · Nature Medicine · doi:10.1038/nm1197-1285 · Cited by 990 · see citing works
Positive and Negative Regulation of IκB Kinase Activity Through IKKβ Subunit Phosphorylation
Delhase, M., Hayakawa, M., Chen, Y., & Karin, M. (1999) · Science · doi:10.1126/science.284.5412.309 · Cited by 852 · see citing works
Self-citationNF-κB-Inducing Kinase Regulates the Processing of NF-κB2 p100
Xiao, G., Harhaj, E. W., & Sun, S. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00187-3 · Cited by 836 · see citing works
The NF-κB Activation Pathway: A Paradigm in Information Transfer from Membrane to Nucleus
Rothwarf, D., & Karin, M. (1999) · Science's STKE · doi:10.1126/stke.1999.5.re1 · Cited by 553 · see citing works
Self-citationJimi, E., Aoki, K., Saito, H., D’Acquisto, F., May, M. J., Nakamura, I., Sudo, T., Kojima, T., Okamoto, F., Fukushima, H., et al. (2004) · Nature Medicine · doi:10.1038/nm1054 · Cited by 500 · see citing works
Macrophage Apoptosis by Anthrax Lethal Factor Through p38 MAP Kinase Inhibition
Park, J. M., Greten, F. R., Li, Z., & Karin, M. (2002) · Science · doi:10.1126/science.1073163 · Cited by 500 · see citing works
Self-citationZhang, Y.-H., Heulsmann, A., Tondravi, M. M., Mukherjee, A., & Abu‐Amer, Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008198200 · Cited by 496 · see citing works
Chen, L.-W., Egan, L. J., Li, Z.-W., Greten, F. R., Kagnoff, M. F., & Karin, M. (2003) · Nature Medicine · doi:10.1038/nm849 · Cited by 483 · see citing works
Self-citationCao, Y., Bonizzi, G., Seagroves, T. N., Greten, F. R., Johnson, R. S., Schmidt, E. V., & Karin, M. (2001) · Cell · doi:10.1016/s0092-8674(01)00599-2 · Cited by 479 · see citing works
Self-citationBaud, V., Liu, Z.-G., Bennett, B. L., Suzuki, N., Xia, Y., & Karin, M. (1999) · Genes & Development · doi:10.1101/gad.13.10.1297 · Cited by 464 · see citing works
Self-citationAlymphoplasia is caused by a point mutation in the mouse gene encoding Nf-κb-inducing kinase
Shinkura, R., Kitada, K., Matsuda, F., Tashiro, K., Ikuta, K., Suzuki, M., Kogishi, K., Serikawa, T., & Honjo, T. (1999) · Nature Genetics · doi:10.1038/8780 · Cited by 451 · see citing works
Inoue, J., Ishida, T., Tsukamoto, N., Kobayashi, N., Naito, A., Azuma, S., & Yamamoto, T. S. (2000) · Experimental Cell Research · doi:10.1006/excr.1999.4733 · Cited by 447 · see citing works
Defective Lymphotoxin-β Receptor-Induced NF-κB Transcriptional Activity in NIK-Deficient Mice
Li, Y., Wu, L., Wesche, H., Arthur, C. D., White, J. M., Goeddel, D. V., & Schreiber, R. D. (2001) · Science · doi:10.1126/science.1058453 · Cited by 408 · see citing works
Bone marrow, cytokines, and bone remodeling
Manolagas, S. C. (1995) · Biomedicine & Pharmacotherapy · doi:10.1016/0753-3322(96)82696-5 · Cited by 388 · see citing works
Rel/NF-κB and IκB proteins: an overview
May, M. J., & Ghosh, S. (1997) · Seminars in Cancer Biology · doi:10.1006/scbi.1997.0057 · Cited by 378 · see citing works
The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4
Hsu, L.-C., Park, J. M., Zhang, K., Luo, J., Maeda, S., Kaufman, R. J., Eckmann, L., Guiney, D. G., & Karin, M. (2004) · Nature · doi:10.1038/nature02405 · Cited by 357 · see citing works
Self-citationBonizzi, G., Bébien, M., Otero, D. C., Johnson-Vroom, K. E., Cao, Y., Vu, D., Jegga, A. G., Aronow, B. J., Ghosh, G., Rickert, R. C., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600391 · Cited by 338 · see citing works
Self-citationGravallese, E. M. (2002) · Annals of the Rheumatic Diseases · doi:10.1136/ard.61.suppl_2.ii84 · Cited by 328 · see citing works
The IκB Function of NF-κB2 p100 Controls Stimulated Osteoclastogenesis
Novack, D., Yin, L., Hagen-Stapleton, A., Schreiber, R. D., Goeddel, D., Ross, F. P., & Teitelbaum, S. L. (2003) · Journal of Experimental Medicine · doi:10.1084/jem.20030116 · Cited by 275 · see citing works
Jimi, E., Nakamura, I., Amano, H., Taguchi, Y., Tsurukai, T., Tamura, M., Takahashi, N., & Suda, T. (1996) · Endocrinology · doi:10.1210/endo.137.8.8754795 · Cited by 198 · see citing works
Tumor Necrosis Factor Receptors Types 1 and 2 Differentially Regulate Osteoclastogenesis
Abu‐Amer, Y., Erdmann, J. M., Alexopoulou, L., Kollias, G. A., Ross, F. P., & Teitelbaum, S. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003886200 · Cited by 195 · see citing works
IKKβ Is Required for Peripheral B Cell Survival and Proliferation
Li, Z., Omori, S. A., Labuda, T., Karin, M., & Rickert, R. C. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.9.4630 · Cited by 192 · see citing works
Self-citationChiang, C., Kyritsis, G., Graves, D. T., & Amar, S. (1999) · Infection and Immunity · doi:10.1128/iai.67.8.4231-4236.1999 · Cited by 178 · see citing works
Wada, N., Maeda, H., Yoshimine, Y., & Akamine, A. (2004) · Bone · doi:10.1016/j.bone.2004.04.023 · Cited by 145 · see citing works
Tsao, D. H. H., McDonagh, T., Telliez, J., Hsu, S., Malakian, K., Xu, G.-Y., & Lin, L.-L. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80270-1 · Cited by 55 · see citing works
Amling, M., Neff, L., Priemel, M., Schilling, A. F., Rueger, J. M., & Baron, R. (2000) · Bone · doi:10.1016/s8756-3282(00)00373-2 · Cited by 48 · see citing works
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Takayanagi, H. (2007) · Nature Reviews Immunology · doi:10.1038/nri2062 · Cited by 1,878 · see citing works
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Frakes, A. E., Ferraiuolo, L., Haidet-Phillips, A. M., Schmelzer, L., Braun, L., Miranda, C. J., Ladner, K. J., Bevan, A. K., Foust, K. D., Godbout, J. P., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.013 · Cited by 638 · see citing works
Greten, F. R., Arkan, M. C., Bollrath, J., Hsu, L.-C., Goode, J., Miething, C., Göktuna, S. I., Neuenhahn, M., Fierer, J., Paxian, S., et al. (2007) · Cell · doi:10.1016/j.cell.2007.07.009 · Cited by 616 · see citing works
Self-citationSirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer
Herranz, D., Muñoz-Martin, M., Cañamero, M., Mulero, F., Martinez-Pastor, B., Fernandez-Capetillo, O., & Serrano, M. (2010) · Nature Communications · doi:10.1038/ncomms1001 · Cited by 612 · see citing works
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Kim, J. H., & Kim, N. (2014) · Journal of Bone Metabolism · doi:10.11005/jbm.2014.21.4.233 · Cited by 570 · see citing works
“[32,33] In the alternative pathway, NF-κB-inducing kinase (NIK) and IKKα phosphorylate and process p100 to generate p52 by proteasomes, resulting in the activation of the p52/RelB complex.[32-35] The important role played by NF-κB proteins in osteoclastogenesis has been verified by the severe osteopetrotic phenotype o…”
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Leibbrandt, A., & Penninger, J. M. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1443.016 · Cited by 420 · see citing works
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- Authors
- Ruocco, M. G., Maeda, S., Park, J. M., Lawrence, T., Hsu, L.-C., Cao, Y., Schett, G., Wagner, E. F., & Karin, M.
- Affiliations
- University of California San Diego (US)
- University of Vienna (AT)
- Research Institute of Molecular Pathology (AT)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2005-05-16
- Volume
- 201
- Issue
- 10
- Pages
- 1677-1687
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2212920
- OpenAlex
- W2153865301
- Cited by
- 252
- References
- 54
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 10 · 2018: 13 · 2017: 5 · 2016: 12 · 2015: 13 · 2014: 15 · 2013: 15 · 2012: 9
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI043477, R37AI043477)
- National Institute of Environmental Health Sciences (R01ES006376)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- IκB kinase β, IkappaB kinase alpha, NF-κB, osteoclast survival, osteoclastogenesis, TNF-α, apoptosis, hematopoietic cells, bone resorption
- MeSH terms
- Animals, Bone Resorption, Carrier Proteins, Cell Differentiation, Cell Survival, Inflammation, Membrane Glycoproteins, Osteoclasts, Protein Precursors, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, Apoptosis, Protein Serine-Threonine Kinases, Mice, Knockout, Myeloid Progenitor Cells, Mice, I-kappa B Kinase, NF-kappa B p50 Subunit, NF-kappa B p52 Subunit, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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